The transplantation of heart grafts can dramatically provide a long and productive life to recipients with heart failure. Typical transplant survivals are more than 10 years. Because of an acute shortage of human donors, however, most do not receive their needed heart graft. Whereas approximately 2300 transplants are performed annually in the United States, it has been estimated that 50,000 could benefit, if a donor were available. In the developed world, the unmet need is estimated at 135,000 transplants per year. The use of donor pigs could readily resolve this severe shortage of organ donors. Pigs can be raised under very clean conditions and would eliminate the risk of spreading human infections and tumors. The physiology of the pig heart is also very similar to human hearts. However, pig heart xenografts are vigorously rejected. With conventional and transgenic donor pigs, increased immune suppression is required to prolong graft survival. This has raised concern about transmission of zoonotic infections to the recipient. The problem is that multiple immune reactions by the host against multiple xenoantigens destroy the graft. Ximerex, Inc. has developed proprietary technology that prevents acute xenograft rejection, including acute vascular rejection, without the need for severe immune suppression. By growing the recipient lymphocytes within donor fetal pigs, the goals of transplantation, specific immune tolerance to the pig and accommodation of the pig tissues, are achieved within the donor animal, before transplantation. Ximerex would process and grow the patient's marrow cells in the donor pig and provide chimeric spleen lymphocytes and an accommodated donor heart to the transplant center. The value of chimeric donor pigs has been demonstrated with pig to sheep heart transplants, including transplants into sensitized sheep with preformed anti-pig antibodies. With modest immune suppression, prolonged graft survival was observed. Furthermore, prolonged survival of pig islets (>150 days) in rhesus macaques was achieved without any post-transplant immune suppression. Heart explants from chimeric pigs demonstrate accommodation with protection against antibodies and complement, including fresh human blood. RNA for proteins associated with accommodation is upregulated in the heart tissue. The proposed SBIR project would complete the preclinical studies required for FDA allowance of phase I/II clinical trials. The Phase I SBIR proposal would establish in pilot studies the efficacy of transplanting chimeric donor pig hearts into non-human primates with hide or no immune suppression. Follow up studies would establish the relative contribution of tissue accommodation and specific immune tolerance to the prolongation of heart xenograft survival.